A low-cost Mr compatible ergometer to assess post-exercise phosphocreatine recovery kinetics.

OBJECTIVE: To develop a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems to reliably quantify metabolic parameters in human lower leg muscle using phosphorus magnetic resonance spectroscopy. MATERIALS AND METHODS: We constructed an MR compatible ergometer using commercially available materials and elastic bands that provide resistance to movement. We recruited ten healthy subjects (eight men and two women, mean age ± standard deviation: 32.8 ± 6.0 years, BMI: 24.1 ± 3.9 kg/m2). All subjects were scanned on a 7 T whole-body magnet. Each subject was scanned on two visits and performed a 90 s plantar flexion exercise at 40% maximum voluntary contraction during each scan. During the first visit, each subject performed the exercise twice in order for us to estimate the intra-exam repeatability, and once during the second visit in order to estimate the inter-exam repeatability of the time constant of phosphocreatine recovery kinetics. We assessed the intra and inter-exam reliability in terms of the within-subject coefficient of variation (CV). RESULTS: We acquired reliable measurements of PCr recovery kinetics with an intra- and inter-exam CV of 7.9% and 5.7%, respectively. CONCLUSION: We constructed a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems, which allowed us to quantify reliably PCr recovery kinetics in lower leg muscle using 31P-MRS.

Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles.

Sphingosine 1-phosphate (S1P) is a potent growth-signaling lipid that has been implicated in cancer progression, inflammation, sickle cell disease, and fibrosis. Two sphingosine kinases (SphK1 and 2) are the source of S1P; thus, inhibitors of the SphKs have potential as targeted cancer therapies and will help to clarify the roles of S1P and the SphKs in other hyperproliferative diseases. Recently, we reported a series of amidine-based inhibitors with high selectivity for SphK1 and potency in the nanomolar range. However, these inhibitors display a short half-life. With the goal of increasing metabolic stability and maintaining efficacy, we designed an analogous series of molecules containing oxadiazole moieties. Generation of a library of molecules resulted in the identification of the most selective inhibitor of SphK1 reported to date (705-fold selectivity over SphK2), and we found that potency and selectivity vary significantly depending on the particular oxadiazole isomer employed. The best inhibitors were subjected to in silico molecular dynamics docking analysis, which revealed key insights into the binding of amidine-based inhibitors by SphK1. Herein, the design, synthesis, biological evaluation, and docking analysis of these molecules are described.